ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Hui-Lung Sun, Ri Cui, JianKang Zhou, Kun-yu Teng, Yung-Hsuan Hsiao, Kotaro Nakanishi, Matteo Fassan, Zhenghua Luo, Guqin Shi, Esmerina Tili, Huban Kutay, Francesca Lovat, Caterina Vicentini, Han-Li Huang, Shih-Wei Wang, Taewan Kim, Nicola Zanesi, Young-Jun Jeon, Tae Jin Lee, Jih-Hwa Guh, Mien-Chie Hung, Kalpana Ghoshal, Che-Ming Teng, Yong Peng, Carlo M. Croce
MicroRNAs (miRNA) are mostly downregulated in cancer. However, the mechanism underlying this phenomenon and the precise consequence in tumorigenesis remain obscure. Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. In liver cancer, the ERK-mediated XPO5 suppression reduces miR-122, increases microtubule dynamics, and results in tumor development and drug resistance. Analysis of clinical specimens further showed that XPO5 phosphorylation is associated with poor prognosis for liver cancer patients. Our study reveals a function of ERK in miRNA biogenesis and suggests that modulation of miRNA export has potential clinical implications.

Teaser

Sun et al. find that ERK phosphorylates XPO5, which induces a Pin1-mediated conformational change that inhibits the ability of XPO5 to load and export pre-miRNA from the nucleus. Phosphorylation of XPO5 is associated with global miRNA downregulation and correlates with poor survival in hepatocellular carcinoma.


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